Post on 12-Jan-2016
Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) trial
Worldwide prevalence of diabetes expected to increase
Diabetes prevalence >171 million in 2000 ~366 million in 2030
World Health Organization, 2000 vs 2030
World Health Organization. www.who.org.
33
15
33
47
36
18
67
4248
120
71
7
0
20
40
60
80
100
120
140
Africa Americas E Medit Europe SE Asia W Pacific
Diabetes prevalence(in millions)
2000 2030
102%
160%
181% 44%
155%
99%
DECODE: IGT increases mortality risk
Diagnosed diabetes (n = 1275)Undiagnosed diabetes (n = 3071)Impaired glucose tolerance (n = 2766)*Normal glucose tolerance (n = 18,252)*
Follow-up (years)
Mortalityhazard
(%)
DECODE Study Group. Lancet. 1999;354:617-21.
*2-hour oral glucose tolerance test (OGTT)IGT = impaired glucose tolerance
Diabetes Epidemiology: Collaborative analysis Of Diagnostic criteria in EuropeN = 25,364 aged ≥30 years
20
10
00 2 4 6 8 10
DPP: Benefit of diet + exercise or metformin on diabetes prevention in at-risk patients
Diabetes Prevention Program (DPP) Research Group. N Engl J Med. 2002;346:393-403.
Years
N = 3234 with IFG/IGT without diabetes
0
0
10
20
30
40
1.0 2.0 3.0 4.0
Placebo
Metformin
Lifestyle
Cumulativeincidence
of diabetes(%)
31%
58%
P*
< 0.001
< 0.001
*vs placeboIFG = impaired fasting glucose
TZDs: Focus on PPAR activation
• Reduces insulin resistance
• Preserves pancreatic β-cell function
• Improves CV risk profile– Improves dyslipidemia (HDL, LDL density, or TG) Renal microalbumin excretion Blood pressure VSMC proliferation/migration in arterial wall PAI-1 levels C-reactive protein levels Adiponectin Free fatty acids
Inzucchi SE. JAMA. 2002;287.360-72.
TRIPOD: Treating insulin resistance reduces incidence of type 2 diabetesTRoglitazone In Prevention Of Diabetesn = 236 Hispanic women with gestational diabetes
60
40
20
0
New-onset diabetes
(%)
Follow-up (months)
0 12 24 36 48 60
Buchanan TA et al. Diabetes. 2002;51:2796-803.
Placebo
Troglitazone 400 mg
12.1%
5.4%
Annual incidence
55% RRRHR 0.45 (0.25–0.83)*
P = 0.009
*Unadjusted
0
TZDs blunt diabetes progression
DPP Research Group.Diabetes. 2005;54:1150-6.*Withdrawn from study after 1.5 yr
Diabetes Prevention Program
10
15
5
1.5
Cumulativeincidence
of diabetes(%)
Years
1.00.50
Placebo
Metformin850 mg bid
Lifestyle
Troglitazone400 mg/d*
23773915682343n =
75% vs placeboP < 0.001
Potential antidiabetic mechanisms of ACE inhibition
Henriksen EJ et al. J Cell Physiol. 2003;196:171-9.
ACE/Kininase II
ACE Inhibitor
Angiotension I
Angiotension II
Bradykinin
Degradation products
BradykininAngiotension II
Nitric oxideSkeletal muscle blood flow
Glucose metabolism
HOPE, EUROPA, PEACE: Reduction in new-onset diabetes
0
2
4
6
8
10
12
14
HOPE EUROPA PEACE Pooled data
New-onset diabetes
(%)
Placebo ACEI
Dagenais GR et al. Lancet. 2006;368:581-8.
N = 23,340 free from diabetes at baseline
Ramipril 10 mg
Perindopril 8 mg
Trandolapril 4 mg
14% RRRRR 0.86 (0.78–0.95)P = 0.0023
(all trials)
Primary outcome:Diabetes or death from any cause
DREAM Trial Investigators. Diabetologia. 2004;47:1519-27.
DREAM: Study design
Secondary outcomes I: CV eventsCombined MI, stroke, CV death, revascularization, HF, angina,
ventricular arrhythmia
Secondary outcomes II: Renal eventsProgression to micro- or
macroalbuminuria, or 30% CrCl
Ramipril 15 mg/d vs placeboAND
Rosiglitazone 8 mg/d vs placebo
Randomized, double-blind 2 × 2 factorial designN = 5269 with IFG and/or IGT, free from CV disease
Follow-up: 3–5 years
Ramipril + Rosiglitazone
DREAM: 2 x 2 factorial design
DREAM Trial Investigators. Diabetologia. 2004;47:1519-27.
N = 5269 with IFG and/or IGT
Ramipril
Rosiglitazone Placebo
Ramipril + Placebo
PlaceboRosiglitazone +
PlaceboPlacebo +Placebo
DREAM: Baseline characteristics
Age (years) 54.7 (±10.9)
Hypertension (%) 43.5
Hyperlipidemia (%) 35.5
BP (mm Hg) 136/83 (±18.6/11.3)
BMI (kg/m2) 30.5 kg/m2 (±5.1)
Waist circumference (inches)
Men 34.3 (±10.8)
Women 32.6 (±11.9)
Glucose (mg/dL)
FPG 104 (±12.6)
2-hour 157 (±25.2)
DREAM Trial Investigators. Diabetologia. 2004;47:1519-27.
DREAM: Rosiglitazone prolongs time to occurrence of new-onset diabetes or death
No. at riskPlaceboRosiglitazone
DREAM Trial Investigators. Lancet. 2006.
26342635
24702538
21502414
11481310
177217
0.6
0.5
0 1 2 3 4
Follow-up (years)
0.4
0.3
0.2
0.1
0.0
Rosiglitazone
Placebo60% RRR HR 0.40 (0.35–0.46) P < 0.0001
Cumulative hazard rate
DREAM: Rosiglitazone decreases new-onset diabetes or death
Rosiglitazone group(n) (%)
Placebo group(n) (%)
Primary outcome composite 306 (11.6%) 686 (26.0%)
Diabetes* 280 (10.6%) 658 (25.0%)
Death* 30 (1.1%) 33 (1.3%)
0.25 1 1.75
P
<0.0001
0.70
<0.0001
DREAM Trial Investigators. Lancet. 2006.
N = 5269
*Participants may appear in both categories
Hazard ratio
Favorsrosiglitazone
Favorsplacebo
DREAM: Regression to normoglycemia with rosiglitazone
26.0
43.7
30.3
11.6
37.9
50.5
0
10
20
30
40
50
60
Diabetes IFG and/or IGT Normal*
Participants (%)
Placebo Rosiglitazone
*FPG < 110 mg/dL DREAM Trial Investigators. Lancet. 2006.
71% increaseHR 1.71 (1.571.87)P < 0.0001
N = 5269
Rosiglitazone effect on weight and BMI
200
196
191
187
182
0
32
31
30
00 01 12 23 34 45 5
Follow-up (years)
lbs kg/m2
Weight BMI
DREAM Trial Investigators. Lancet. 2006.
Rosiglitazone Placebo
P < 0.0001 P < 0.0001
0.94
0.92
0.90
0.88
0
115
107
99
00 01 12 23 34 45 5
cm
WHR Circumference
Rosiglitazone effect on waist and hip measurements
111
103
95
P < 0.0001
P = NS
P < 0.0001
Waist
Hip
Follow-up (years)
DREAM Trial Investigators. Lancet. 2006.WHR = Waist-hip ratio
Rosiglitazone Placebo
Rosiglitazone
Placebo
Follow-up (months)
ALT (U/L)P <0.0001
Effect on ALT
0
24
26
28
30
Baseline 2 4 6 8 10 12
DREAM: Rosiglitazone and hepatic enzymes
DREAM Trial Investigators. Lancet. 2006.ALT = alanine aminotransferase
DREAM: Ramipril demonstrates neutral effect on new-onset diabetes or death
DREAM Trial Investigators. N Engl J Med. 2006.
Placebo
Ramipril
No. at riskPlaceboRamipril
Follow-up (years)
0.6
0.5
0.4
0.3
0.2
0.1
0.00 1 2 3 4
26462623
25102498
22772287
12401218
200194
9% RRRHR 0.91 (0.81–1.03)
P = 0.15
Cumulative hazard rate
DREAM: Ramipril effect on glycemic categories
18.5
43.3
38.2
17.1
40.342.6
0
5
10
15
20
25
30
35
40
45
Diabetes IGT or IFG Normoglycemia
Patients (%)
Placebo Ramipril
P = 0.006
DREAM Trial Investigators. N Engl J Med. 2006.
DREAM: SafetyRosiglitazone vs placebo• Increased incidence of HF* (0.5% vs 0.1%, P = 0.01)
– No cases of fatal HF– No difference for other CV events
• Increased incidence of peripheral edema(6.8% vs 4.9%, P = 0.003)
• 4.9-lb weight gain (P < 0.0001)– Increased hip circumference (0.71 in, P < 0.0001)– No difference in waist circumference – Decreased waist-hip ratio (P < 0.0001)
• No adverse hepatic effects – ALT levels 4.2 U/L at 1 year (P < 0.0001)
Ramipril vs placebo• Increased incidence of confirmed HF* (0.5% vs 0.2%)
• No adverse hepatic effects– ALT levels 1.1 U/L at 1 year (P = 0.004)
DREAM Trial Investigators. Lancet. 2006; N Engl J Med. 2006. *Adjudicated
DREAM results: Summary
Rosiglitazone• 60% RRR in new-onset diabetes or death (P < 0.001)
NNT = 7
• Benefit observed regardless of ethnicity, sex, age, weight, and fat distribution
• Increased regression to normoglycemia* vs placebo (50.5% vs 30.3%)(HR 1.71, P < 0.0001)
Ramipril• 9% RRR in new-onset diabetes or death (nonsignificant)
• Increased regression to normoglycemia* vs placebo (42.6% vs 38.2%)(HR 1.16, P = 0.001)
DREAM Trial Investigators. Lancet. 2006; N Engl J Med. 2006.
*FPG < 110 mg/dL and 2-h glucose < 141 mg/dL